<p>Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer</p>

Abstract

The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy. Methods: An ion-pairing complex of OP with a permeation enhancer, N α-deoxycholyl-L-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF). Results: The optimized powder formulation was sized in the nanoscale range (133±1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls. Conclusion: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.

Coordinated ASBT and EGFR Mechanisms for Optimized Liraglutide Nanoformulation Absorption in the GI Tract

“…These inhibitors were chosen due to their documented effects on endocytic and exocytic pathways. 15 , 38 Caco-2 cells were plated on a 12 mm Transwell ® plate with a 0.4 µm pore membrane at 1 × 10 5 cells/well density and cultured until reaching a TEER value between 250 and 300 Ω·cm 2 . Then, 1 h before drug treatment, the HBSS was substituted with fresh medium.…”

“…Beyond facilitating the absorption of fats and lipids, they act as potent drug carriers, amplifying the uptake of pharmaceuticals. [15][16][17] A variety of injectable medications, including anti-cancer agents, insulin, and heparin, have been paired with such derivatives to develop oral formulations. Such preparations have consistently proven to enter the lymphatic or systemic circulation, showing bolstered oral bioavailability.…”

Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives

“…The particle size of the optimized powder formulation was obtained within the nanoscale range (133 ± 1.47 nm). In both animal models, the findings revealed considerable enhancement in oral absorption in addition to the extensive impedance of tumor growth via metronomic dosing [54]. Furthermore, research done by Cai and colleagues assessed the anti-angiogenic and anti-tumor efficacy of novel zoledronic acid-loaded liposomes via metronomic scheduling in a mouse model.…”

Normalizing tumor microenvironment with nanomedicine and metronomic therapy to improve immunotherapy

“…Interestingly, apart from CRLX101, a few other nanoparticle formulations, which have not reached clinical testing yet, have also shown normalization effects similar to metronomic therapy in preclinical studies [ 29 , 37 , 38 ]. Of note is the metronomic administration of nanoparticles containing oxaliplatin that leads to increased antitumor efficacy compared to free oxaliplatin metronomic treatment [ 39 , 40 ]. A key to the effectiveness of both approaches compared to MTD is that they can potentially maintain effective drug levels in the blood for long duration.…”